The PI of this K23 application is a physician-scientist with a career focus on developing improved care for patient with Pulmonary Arterial Hypertension (PAH), a rare but debilitating and fatal disease for which there is currently no available cure. Current treatment options target the cellular dysfunction that leads to constriction of the vasculature and produce pulmonary vasodilation. While these agents limit clinical deterioration and lower pulmonary pressures, their ability to produce, retard or reverse frank vascular remodeling is limited. Accumulating evidence suggests that carbon monoxide (CO) confers potent cytoprotection via anti-inflammatory, anti-proliferative and anti-apoptotic effects, processes critical for repair and remodeling of injured tissues, including those found in PAH. Specifically, exogenous delivery of inhaled CO prevents and reverses established PAH in multiple animal models. Within a highly mentored training program with staggering expertise available to the PI with the PI's mentor and Advisory Committee, the PI will explore the development and utilization of CO-based therapies that target PAH pathobiological processes. The hypotheses tested include: i) inhaled CO regulates physiologic, cellular and molecular pathways in patients with PAH which result in attenuation of pulmonary vascular remodeling; ii) a molecular signature can be defined in peripheral blood mononuclear leukocytes (PBMCs) which predict CO responsiveness. To address these hypotheses, in Specific Aim #1 the PI will conduct a phase I trial to establish safety and efficacy of inhaled CO when added to standard therapy in patients with severe PAH. Specific Aim #2 will define a genomic signature in PBMCs as biomarkers of responsiveness to CO inhalation in patients with severe PAH. In Specific Aim #3 we will prospectively validate the utility of the PBMC molecular signature as a biomarker of a beneficial response to CO therapy in patients with severe PAH. Together, these studies provide an outstanding curriculum for the PI to receive essential training in clinical research and develop skills in novel, highly translational approaches which will identify novel targets and biomarkers and may lead to better treatment options for patients with PAH.